Poor regeneration of functional dopaminergic neurons (DA) is one of the most common healthcare challenges for Parkinson’s Disease (PD) patients. In contrast to mammals, zebrafish has an amazing potential to repair their dopaminergic neurons (DA) after injury. However, the molecular mechanisms that regulate these reparative events remain to be determined. To address this, we compared the temporal changes in key transcription factors (TFs), which regulate the developmental trajectories of DA neurons during injury and regeneration in zebrafish. MPP⁺ was exposed to zebrafish embryos between 18 Hpf and 96 Hpf to create a model of DA injury and regeneration after injury (1day, 2days, 3 days, 4 days, 5 days, 6 days, 7 days and 87 days post DA injury). During time series of MPP⁺ exposure, we found temporal alterations in the expression patterns of TFs; Nurr1, Foxa1, Lmx1a/b and En1/2 using WISH and RT-PCR. This turning point in expression dynamics coincided with a DA phenotypic turning point, as shown by 50% decline in TH⁺/DAT⁺ neurons and locomotor activity in the days following the MPP⁺ exposure. Using this model, we demonstrate for the first time that zebrafish are capable of regenerating a functional DA phenotype after 50% DA ablation. Following acute DA injury, mRNA levels of most TFs started to increase between 3-8 days after injury which was significantly elevated to normal levels in adult zebrafish brain i.e. at 87^th day after injury. Remarkably, the changes in mRNA expression of TFs temporally correlate with corresponding increase in TH/DAT expression and functional recovery. Taken together, this study showed a highly relevant role of TFs for dopamine producing neurons during regeneration of DA neurons following ablation with restoration of normal behavior. This study implies that TFs as potential therapeutic targets for enhancing regeneration of DA neurons in mammalsobserved over.

中文翻译：

---

MPP +诱导斑马鱼脑损伤和恢复期间多巴胺神经元关键发育转录因子的时间变化

功能性多巴胺能神经元（DA）再生差是帕金森氏病（PD）患者最常见的医疗保健挑战之一。与哺乳动物相反，斑马鱼在受伤后具有修复其多巴胺能神经元（DA）的惊人潜力。然而，调节这些修复事件的分子机制仍有待确定。为了解决这个问题，我们比较了关键转录因子（TFs）的时间变化，这些转录因子调节斑马鱼在损伤和再生过程中DA神经元的发育轨迹。MPP ⁺暴露于18 Hpf至96 Hpf之间的斑马鱼胚胎中，以建立DA损伤和损伤后再生的模型（DA损伤后1天，2天，3天，4天，5天，6天，7天和87天） 。在MPP ^+的时间序列中暴露，我们发现TFs表达模式的时间变化；使用WISH和RT-PCR检测Nurr1，Foxa1，Lmx1a / b和En1 / 2。表达动力学的这一转折点与DA表型转折点相吻合，如MP ⁺暴露后几天TH ⁺ / DAT ⁺神经元和运动活性下降50％所示。使用该模型，我们首次证明了斑马鱼在50％DA消融后能够再生功能性DA表型。急性DA损伤后，大多数TF的mRNA水平在损伤后3-8天之间开始增加，在成年斑马鱼脑中（即在^第87天）显着升高至正常水平受伤后的第二天。值得注意的是，TFs mRNA表达的变化与TH / DAT表达和功能恢复的相应增加在时间上相关。两者合计，这项研究表明TFs在消融后DA神经元再生并恢复正常行为的过程中，对多巴胺产生神经元具有高度相关的作用。这项研究表明，TFs是增强哺乳动物DA神经元再生的潜在治疗靶标。